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Biomedical subjects

S D Shafran

Publications and source records attributed to S D Shafran.

At least 19 recordsLinked to original sources
PubMed2000

Symptomatic and health status outcomes in the Canadian randomized MAC treatment trial (CTN010). Canadian HIV Trials Network Protocol 010 Study Group.

Our objective was to compare the effect of 2 regimens for treatment of Mycobacterium avium complex (MAC) bacteraemia in an HIV-positive population on symptoms and health status outcomes using a substudy of an open-label randomized controlled trial. The study was conducted in 24 hospital-based human immunodeficiency virus (HIV) clinics in 16 Canadian cities. Patients had HIV infection and MAC bacteraemia and were given either rifampin 600 mg, ethambutol 15 mg/kg daily, clofazimine 100 mg daily and ciprofloxacin 750 mg twice daily (4-drug arm) or rifabutin 600 mg daily (amended to 300 mg daily in mid-trial), ethambutol 15 mg/kg daily and clarithromycin 1000 mg twice daily (3-drug arm). The primary health status outcome was the change on the 8-item symptom subscale of the Medical Outcome Study (MOS)-HIV Health Survey adapted for MAC. Changes on other MOS-HIV subscales and on the Karnofsky score were also evaluated. Patients on the 3-drug arm had better outcomes on the MOS-HIV symptom subscale at 16 weeks (P=0.06), with statistically significant differences restricted to night sweats and fever and chills (P < 0.001). The proportion of patients improving on the symptom subscale relative to baseline was 55% on the 3-drug arm and 40% on the 4-drug arm. Patients on the 3-drug arm also had better Karnofsky score at 16 weeks (P < 0.001) and better outcomes on the social function, mental health, energy/fatigue, health distress and cognitive function subscales of the MOS-HIV. The 3-drug arm is superior to the 4-drug arm in terms of impact on MAC-associated symptoms, functional status and other aspects of health status.

AIDS-Related Opportunistic Infections↗
PubMed1999

Predictors of survival and eradication of Mycobacterium avium complex bacteremia (MAC) in AIDS patients in the Canadian randomized MAC treatment trial. Canadian HIV Trials Network Protocol 010 Study Group.

OBJECTIVE: To assess the importance of baseline characteristics including medical history, indicators of current disease status, therapeutic drug use, in vitro drug susceptibility, immune status and mycobacterial load on bacteriologic response and survival in HIV-positive patients with Mycobacterium avium complex (MAC) bacteremia. DESIGN: An observational substudy of an open-label randomized controlled trial of two alternative therapeutic regimens for MAC. SETTING: Twenty-four hospital-based HIV clinics in 16 Canadian cities. MAIN OUTCOME MEASURES: The main outcome measures were survival and bacteriologic response, defined by consecutive negative blood cultures for MAC at least 2 weeks apart within 16 weeks of study entry. RESULTS: Prior AIDS diagnosis, low Karnofsky score, active unstable AIDS-related conditions, absence of antiretroviral therapy and absence of Pneumocystis carinii pneumonia prophylaxis were associated with shorter survival by univariate regression using the proportional hazards model. On multivariate analysis, antiretroviral therapy was not an independent predictor of mortality, and previous rifabutin prophylaxis was independently associated with poor survival outcomes, a result consistent across study treatment. Using a logistic regression model, baseline quantitative mycobacterial load [relative odds of clearing, 1.97 for a decrease of 1 log10 colony forming count; 95% confidence interval (CI), 1.36-2.87; P < 0.001] and Karnofsky score were the only statistically significant univariate predictors of clearance, although previous prophylaxis with rifabutin was also a significant predictor in a multivariate model (relative odds of clearing, 0.39; 95% CI, 0.17-0.88; P < 0.05). CONCLUSIONS: This study indicates that although the level of MAC bacteremia is an important predictor of clearance, it is not associated with survival.

AIDS-Related Opportunistic Infections↗
PubMed1999

A randomized, placebo-controlled study of rifabutin added to a regimen of clarithromycin and ethambutol for treatment of disseminated infection with Mycobacterium avium complex.

Current guidelines suggest that disseminated Mycobacterium avium complex (MAC) infection be treated with a macrolide plus ethambutol or rifabutin or both. From 1993 to 1996, 198 AIDS patients with MAC bacteremia participated in a prospective, placebo-controlled trial of clarithromycin (500 mg b.i.d.) plus ethambutol (1,200 mg/d), with or without rifabutin (300 mg/d). At 16 weeks, 63% of patients in the rifabutin group and 61% in the placebo group (P = .81) had responded bacteriologically. Changes in clinical symptoms and time to survival were similar in both groups. Development of clarithromycin resistance during therapy was similar in the two groups; of patients who had a bacteriologic response, however, only 1 of 44 (2%) receiving rifabutin developed clarithromycin resistance, vs. 6 of 42 (14%) in the placebo group (P = .055). Thus, rifabutin had no impact on bacteriologic response or survival but may protect against development of clarithromycin resistance in those who respond to therapy.

AIDS-Related Opportunistic Infections↗
PubMed1998

Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group.

CONTEXT: Recurrent genital herpes simplex virus (HSV) may be treated episodically, but this may not be sufficient for patients with frequent recurrences. OBJECTIVE: To determine the efficacy and safety of famciclovir in the suppression of recurrent genital HSV infection. DESIGN: A randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Thirty university, hospital, or private outpatient referral centers in Canada and Europe. PATIENTS: A total of 455 patients (223 men, 232 women) aged 18 years or older with a history of 6 or more episodes of genital herpes during 12 of the most recent 24 months, in the absence of suppressive therapy, received study medication. INTERVENTION: Oral famciclovir, 125 mg or 250 mg 3 times daily or 250 mg twice daily, or placebo for 52 weeks. MAIN OUTCOME MEASURES: Time to the first recurrence of genital HSV infection; the proportion of patients remaining free of HSV recurrence at 6 months; frequency of adverse events. RESULTS: In an intent-to-treat analysis, famciclovir significantly delayed the time to the first recurrence of genital herpes at all dose regimens (hazard ratios, 2.9-3.3; P<.001); median time to recurrence for famciclovir recipients was 222 to 336 days compared with 47 days for placebo recipients. The proportion of patients remaining free of HSV recurrence was approximately 3 times higher in famciclovir recipients (79%-86%) than in placebo recipients (27%) at 6 months (relative risks, 2.9-3.1; P<.001); efficacy was maintained at 12 months. Famciclovir was well tolerated with an adverse experience profile comparable to placebo. CONCLUSIONS: Oral famciclovir (125 mg or 250 mg 3 times daily or 250 mg twice daily) is an effective, well-tolerated treatment for the suppression of genital HSV infection in patients with frequent recurrences.

2-Aminopurine↗
PubMed1998

Estimating the effect of treatment on quality of life in the presence of missing data due to drop-out and death.

Quality of life was measured in a study of two multidrug regimens for mycobacterium avium complex MAC bactaeremia using the MOS-HIV questionnaire. The effect of treatment on quality of life was estimated at each follow-up time in three ways: (1) using only the observed data, (2) after assigning the worst possible quality of life scores for individuals who died, and (3) after imputing missing scores for patients who either died or dropped out of the study. The overall quality of life scores were also compared between treatment groups with categorical generalized estimating equation models and three-dimensional graphs. Of the 179 patients included in these analyses, 84 (47%) either died or dropped out during the 16 week study period. When the quality of life scores were compared between the treatment groups with the Wilcoxon rank sum test using only the observed data, there was no significant difference between the groups at 16 weeks of follow-up. When the worst possible quality of life scores were assumed for patients who had died, both the magnitude and the statistical significance of the difference in the quality of life scores between the groups increased. Imputing missing data for patients who either dropped out or died resulted in even larger differences in quality of life between the treatment groups. We conclude that ignoring missing data due to drop-outs and death can result in an underestimation of the treatment effect and overly optimistic statements about the outcome of the participants on both treatment arms due to the selective drop-out of participants with poorer quality of life. To obtain a valid assessment of the effect of treatment on quality of life, the experience of the patients who died or dropped out of the study must be considered.

AIDS-Related Opportunistic Infections↗
PubMed1998

Does in vitro susceptibility to rifabutin and ethambutol predict the response to treatment of Mycobacterium avium complex bacteremia with rifabutin, ethambutol, and clarithromycin? Canadian HIV Trials Network Protocol 010 Study Group.

The in vitro susceptibilities of baseline Mycobacterium avium complex (MAC) blood isolates from 86 patients with AIDS who were treated with clarithromycin, ethambutol, and rifabutin were determined to examine whether these results predict bacteriologic response to treatment. No patient received prior prophylaxis with clarithromycin or azithromycin. Minimum inhibitory concentrations (MICs) of clarithromycin for all isolates were < or = 2 micrograms/mL. The median MIC of rifabutin was between 0.25 and 0.5 microgram/mL, and all isolates were susceptible to < or = 2 micrograms of rifabutin/mL. The median MIC of ethambutol was 4 micrograms/mL, and the MIC90 was 8 micrograms/mL. There was no correlation between ethambutol susceptibility and subsequent bacteriologic clearance. At all time points through week 12, bacteriologic clearance occurred more frequently in patients with isolates for which MICs of rifabutin were lower, but this difference was statistically significant only at week 2. Susceptibility testing for baseline MAC isolates from AIDS patients not previously treated with clarithromycin or azithromycin does not appear to be useful in guiding therapy.

AIDS-Related Opportunistic Infections↗
PubMed1998

Determinants of rifabutin-associated uveitis in patients treated with rifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteremia: a multivariate analysis. Canadian HIV Trials Network Protocol 010 Study Group.

Uveitis occurred in a substantial proportion of AIDS patients receiving rifabutin, 600 mg daily, together with clarithromycin and ethambutol for treatment of Mycobacterium avium complex bacteremia. A case-control study was undertaken to examine potential risk factors for developing uveitis. Of eight parameters examined, only baseline body weight predicted the development of uveitis by both univariate and multivariate analyses (P = .001). The incidence of uveitis was 14% in patients weighing >65 kg, 45% in patients between 55 and 65 kg, and 64% in patients <55 kg. Concomitant therapy with fluconazole, a drug known to raise serum rifabutin concentrations, was not associated with an increased incidence of uveitis. The risk of uveitis was markedly reduced when rifabutin was given at 300 mg daily in combination with clarithromycin and ethambutol.

AIDS-Related Opportunistic Infections↗
PubMed1998

A multicenter phase I/II dose escalation study of single-dose cidofovir gel for treatment of recurrent genital herpes.

A randomized, double-blind, clinic-initiated, sequential dose-escalation pilot study was performed to compare the safety and efficacy of single applications of 1, 3, and 5% cidofovir gel with placebo in the treatment of early, lesional, recurrent genital herpes at five Canadian outpatient sites. Ninety-six patients began treatment within 12 h of lesion appearance and were evaluated twice daily until healing of the lesion occurred. Cidofovir gel at all strengths significantly decreased the median time to negative virus culture in a dose-dependent fashion (3.0 days in the placebo group versus 2.2, 1.3, and 1.1 days in the 1, 3, and 5% cidofovir gel treatment groups, respectively; P = 0.02, 0.0001, and 0.0003, respectively). A trend toward a reduction in the median time to complete healing in association with treatment was present, but the differences were not statistically significant (5.0 days in the placebo group versus 4.3, 4.1, and 4.6 days in the 1, 3, and 5% cidofovir gel treatment groups, respectively). Application site reactions occurred in 3, 5, 19, and 22% of the patients in these four groups, respectively. Treatment-associated lesion recrudescence with delayed healing, which is suggestive of local toxicity, was observed in three patients treated with 5% cidofovir gel and one patient treated with 3% cidofovir gel. In summary, single-dose application of cidofovir gel confers a significant antiviral effect on lesions of recurrent genital herpes. Additional studies are warranted to further identify the optimal efficacious dose of cidofovir in association with the maximum gel strength that can be tolerated.

Adult↗
PubMed1997

Topical undecylenic acid for herpes simplex labialis: a multicenter, placebo-controlled trial.

A multicenter, patient-initiated, double-blind, placebo-controlled trial of 15% undecylenic acid cream was conducted with 573 patients with recurrent herpes labialis. Treatment was applied 5 or 6 times daily until crusting and then thrice daily until healing. Patients were assessed daily until 48 h after crusting and then every other day until healing. Undecylenic acid significantly reduced the incidence and duration of viral shedding and the duration and severity of itching but did not increase abortive episodes or reduce times to healing, crusting, or progression of lesion size. When treatment was initiated during the prodrome, the time to crusting was reduced (P = .02) and the area under the symptom-time curve for pain and tenderness was reduced, approaching statistical significance (P = .06). Active treatment was well tolerated but caused dysgeusia and local irritation. Undecylenic acid 15% cream reduces viral shedding in recurrent herpes labialis, but clinical benefits are minimal and largely restricted to patients initiating therapy during the prodrome.

Administration, Topical↗
PubMed1997

Comparison of dose doubling with probenecid for sustaining serum cefuroxime levels.

Serum cefuroxime concentrations were measured over a 12 h period in ten healthy adults following three iv dosing regimens: 750 mg cefuroxime, 1.5 g cefuroxime, and 750 mg cefuroxime with 1 g of probenecid given orally 3 h before the cefuroxime infusion. Probenecid prolonged the serum cefuroxime half-life by 63% (P < 0.05) with a significant increase in the mean time for which serum cefuroxime concentrations exceeded the MIC90 for common respiratory pathogens (2 mg/L) compared with either 750 mg cefuroxime (2.2 h, P < 0.05) or 1.5 g of cefuroxime (0.9 h, P < 0.05) without probenecid. The cost of the 750 mg cefuroxime dose plus probenecid is approximately half that of a 1.5 g cefuroxime dose.

Adolescent↗
PubMed1996

Dapsone- and primaquine-induced methemoglobinemia in HIV-infected individuals.

Clinically significant methemoglobinemia can develop as a result of medications. Although dapsone and primaquine are known to produce methemoglobinemia in susceptible individuals, methemoglobinemia has been reported only rarely in the human immunodeficiency virus (HIV) population. We describe five cases of methemoglobinemia caused by either primaquine or dapsone alone or in combination. The initial methemoglobin level ranged from 15.3% in the patient whose methemoglobinemia was caused by primaquine alone to 33.1%. Five patients developed symptomatic methemoglobinemia requiring hospitalization for 1 to 12 days. Two cases resulted from intentional overdoses of dapsone, and three developed within several days of commencing primaquine while dapsone remained present in the bloodstream. The four severe cases required intravenous methylene blue, supplemental oxygen, plus erythrocyte transfusions, whereas the mild case responded to oxygen therapy plus discontinuation of the precipitating drugs. Blood gases and pulse oximetry do not aid in the diagnosis, which requires cooximetry. Our study indicates that dapsone and primaquine alone or in combination can produce clinically significant methemoglobinemia in HIV-infected individuals, either in the setting of an overdose or when primaquine is instituted before dapsone has been cleared from the bloodstream.

AIDS-Related Opportunistic Infections↗
PubMed1996

A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group.

BACKGROUND: Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. METHODS: We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. RESULTS: Among 187 patients who could be evaluated, blood cultures became negative more often in the three-drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P=0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). CONCLUSIONS: In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better.

AIDS-Related Opportunistic Infections↗
PubMed1996

Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study Group.

OBJECTIVE: To compare the efficacy and safety of episodic patient-initiated oral famciclovir with placebo in recurrent genital herpes. DESIGN: Randomized, double-blind, frequent-observation, dose-ranging study comparing twice-daily 125-mg, 250-mg, or 500-mg oral famciclovir with placebo. Patients initiated therapy after self-culturing, reported to the clinic within 12 hours, and were assessed twice daily for at least 5 days. SETTING: Fifteen Canadian university, private practice, or public outpatient clinics. PATIENTS: A total of 692 patients with culture-proven recurrent genital herpes were randomized; 467 patients experienced a symptomatic episode and commenced treatment. MAIN OUTCOME MEASURE: Time to complete healing of all lesions. RESULTS: Famciclovir (all doses) was significantly more effective than placebo in reducing time to healing, time to cessation of viral shedding, and durations of lesion edema, vesicles, ulcers, and crusts. Times to cessation of all symptoms and of moderate to severe lesion tenderness, pain, and burning were also reduced. Patients who initiated famciclovir prior to viral shedding were more likely to not shed virus throughout. All doses were equally effective, safe, and well tolerated. CONCLUSIONS: Oral famciclovir reduced the onset and duration of viral shedding, lesion persistence, and uncomfortable symptoms. Several individual symptoms and lesion stages were also reduced in duration by this episodic therapy. Additionally, our twice-daily observation trial design proved to be a helpful tool for studying recurrent disease. Episodic oral famciclovir provides a convenient and effective alternative for those patients with recurrent genital herpes whose frequency rates do not require continuous antiviral suppression.

2-Aminopurine↗
PubMed1996

Infective endocarditis: review of 135 cases over 9 years.

One hundred thirty-five cases of infective endocarditis in adults at the University of Alberta Hospital from 1985 to 1993 were reviewed and the von Reyn and Duke criteria were compared. There were 80 cases of native valve endocarditis, 15 cases of endocarditis in intravenous drug users, 7 cases of early prosthetic valve endocarditis, and 33 cases of late prosthetic valve endocarditis. Valve replacement or repair was performed in 33% of all cases. The overall mortality was 19%. The mortality among patients treated surgically was significantly lower than that among those treated medically (9% vs. 24%, respectively; P = .037). However, when patients who were too medically unstable for surgery or who refused surgery were excluded, the mortality among the medically treated group decreased to 15%, which was not significantly different from that among the surgically treated group. The 33 patients transferred from other hospitals were infected with similar pathogens; however, the rate of surgical intervention among these patients was much higher than that among other patients (64% vs. 24%, respectively; P < .0001), and the mortality was slightly lower (12.1% vs. 21.6%, respectively; P = .31). The 54 surgical and autopsy-proven cases were classified by the von Reyn and the Duke criteria without knowledge of the operative and autopsy results: 15% of these cases were rejected by the von Reyn criteria, and none were rejected by the Duke criteria.

Adolescent↗
PubMed1995

Disseminated Mycobacterium genavense infection in Canadian AIDS patients.

Mycobacterium genavense is a recently described mycobacterial species which thus far has been identified only in persons with advanced HIV disease. It appears to be a rare pathogen with an undefined reservoir. We describe the first two cases of M. genavense infection in Canadian AIDS patients. The clinical presentation of fever and wasting with extremely low CD4 lymphocyte counts was indistinguishable from disseminated M. avium complex (MAC) infection. However, blood cultures in BACTEC 13A medium required a mean of 58 days (range 41-87) to detect growth of M. genavense in contrast to a mean of 10 days for MAC in our laboratory. M. genavense infection is underdiagnosed due to the lack of universal use of BACTEC liquid medium and the use of relatively short incubation times (only 6 weeks) by some laboratories. The value of antimycobacterial therapy for M. genavense is unknown, but anecdotal data suggest that treatment with a regimen appropriate for MAC may be beneficial.

Acquired Immunodeficiency Syndrome↗